1. Field of the Invention
The present invention relates to a composition and method for the flushing and coating of catheters for the prevention of infection and blood coagulation.
2. Description of Related Art
Hemodialysis access systems for access to a human or animal patient's vascular system for exchange of blood between the vascular system and an external processing apparatus are well known in the art. One method comprises a catheter placed in the patient with one end extending into the central venous system. As with any invasive procedure, the prevention of infection has been a problem, particularly with a device that must remain in place over protracted periods of time. Coagulation of the blood in and around the catheter has also proven troublesome and methods are needed for its prevention, particularly with regard to inhibiting the clogging of the catheter, which can diminish or destroy its usefulness. A significant amount of research has been directed to the alleviation of these problems.
It is standard procedure to flush catheters with an anticoagulant, such as heparin. However, heparin is not an antibacterial and, in addition, if not carefully controlled, it can carry the anti-coagulation process too far, thereby presenting a risk of hemorrhage.
U.S. Pat. No. 4,096,241 discloses pharmaceutical compositions for the treatment and for prophylaxis of tooth and gum infections, and in particular parodontosis, comprising derivatives of thiadiazine as the active ingredient.
U.S. Pat. No. 4,107,305 discloses a method of combating endotoxaemia by administering an effective amount of a taurolin composition.
U.S. Pat. No. 4,337,251 discloses the use of taurolin in humans or animals to eliminate or reduce adhesions after surgery.
U.S. Pat. No. 4,587,268 discloses a composition for the treatment of wounds comprising a resorbable aqueous gel having dissolved or dispersed therein one or more water-soluble medicaments, which are preferably an antibiotic or a methylol transfer antibacterial.
U.S. Pat. No. 4,587,284 discloses the preparation of an enhanced water-absorbency hydrophilic polymer material, suitable for use in wound dressings by a process in which a water-containing organic hydrogel comprising a gelable polysaccharide and/or protein or polypeptide interspersed with a polymer of a hydrophilic acrylic or methacrylic acid derivative is permeated with a base, the pH of said hydrogel being raised to at least 9 during treatment with said base.
U.S. Pat. No. 4,604,391 discloses the administration of taurolin compounds prophylactically to humans or warm-blooded animals to combat the occurrence of osteitis or osteomyelitis, especially in patients suffering from bone injuries of traumatic origin.
U.S. Pat. No. 4,626,536 discloses the use of taurolin compounds to combat toxic proteins or peptides, e.g., venoms, fungal toxins and bacterial exotoxins, in the bloodstream of humans or warm-blooded animals.
U.S. Pat. No. 4,772,468 discloses a pharmaceutical composition for filling into bone cavities comprising an aqueous paste formed from powdered calcium phosphate and an antibacterial substance, if necessary together with one or more binders. The antibacterial substance is preferably taurolidine and the calcium phosphate is preferably .beta.-tricalcium phosphate.
U.S. Pat. No. 4,797,282 discloses a drug depot, which can be implanted in the body, for the controlled, delayed release of cytostatics, comprising a synthetic material based on polyacrylates and/or polymethacrylates containing a cytostatic and at least one amino acid.
U.S. Pat. No. 4,853,225 discloses an implantable medicament depot useful for combating infections comprising physiologically acceptable excipients and at least one delayed release active compound that is a chemotherapeutic of the gyrase inhibitor type.
U.S. Pat. No. 4,882,149 discloses a pharmaceutical depot preparation for implantation into base tissue comprising natural bone mineral from which the naturally associated fat and bone-proteins have been removed whereby said bone is sterile and non-allergenic, said bone material having adsorbed thereon and/or absorbed therein one or more physiologically active substances. The physiologically active substance is advantageously an antibiotic or taurolidine or taurultam or a protein or polypeptide assisting bone regeneration.
U.S. Pat. No. 4,905,700 discloses an acoustic coupling medium for transmitting ultra-sound. The medium, which is of use in ultrasonic visualization of the human body, comprises a sheet of hydrogel containing over 90% water, preferably over 95% water. The hydrogel preferably comprises agar, the chains of which are interspersed with chains of polyacrylamide.
U.S. Pat. No. 4,960,415 discloses a device for inserting in wounds and wound cavities consisting of a container containing a pharmaceutically active substance, the walls of this container consisting at least partly of a membrane, preferably a semi-permeable membrane, which allows the active substance to escape into the wound area. The container is, more preferably, a dialysis tube. In order to drain off wound secretions, the container containing the pharmaceutically active substance, particularly taurolidine, is conveniently connected to a drainage tube. Preferably, a drainage tube is used in which the end that leads into the wound is split into filaments.
U.S. Pat. No. 5,077,281 discloses the use of taurolin compounds as blood coagulation-inhibiting agents and as abacterial inflammation-inhibiting agents. According to the patent, taurolin has outstanding coagulation-inhibiting action and is especially suitable for use in medical conditions requiring dialysis and for vascular prostheses. It is also disclosed that these compounds can be used together with other anti-coagulants such as coumarin or heparin.
U.S. Pat. No. 5,167,961 and 5,417,975 disclose processes for the preparation of high purity bone mineral wherein the organic matter is degraded by heating with ammonia or a primary amine, characterized in that the solubilized degradation products are extracted by washing with flowing water at a temperature below 60.degree. C., such heating with primary amine and washing steps optionally being repeated, whereby substantially all organic matter removable by these steps is removed, the bone mineral so treated being heated in air at temperatures up to 700.degree. C.
U.S. Pat. No. 5,210,083 discloses an aqueous solution containing a bacterially effective concentration of taurolidine and/or taurultam together with a parenterally acceptable polyol. The aqueous solution is said to be particularly suitable for parenteral administration.
U.S. Pat. No. 5,362,754 discloses pharmaceutical compositions of a mixture of minocycline and EDTA (M-EDTA) and methods of using the compositions in maintaining the patency of a catheter port. Methods for inhibiting the formation of polysaccharide-rich glycocalyx (such as the glycocalyx of staphylococcal organisms) are also provided using an M-EDTA solution. The M-EDTA solution may also be used to pretreat a medical device to prevent adherence of infectious organisms, such as S. epidermis and S. aureous. The compositions destroy and prevent the formation of polysaccharide-rich glycocalyx.
U.S. Pat. No. 5,573,771 discloses a purified particulate bone mineral product for use in medicine, the particles of said mineral being substantially free from all endogenous organic material and having at least at the surface thereof resorbable, physiologically compatible, natural or synthetic macromolecular material. In particular, a bone mineral is provided that is impregnated with a gel-forming protein or polysaccharide such as gelatin to provide an increase in strength and a product comprising bone mineral in a matrix of collagen-fibers and a gel-forming protein. Such products are intended as remodeling implants or prosthetic bone replacement.
U.S. Pat. No. 5,593,665 discloses products containing tumor necrosis factor and taurolidine and/or taurultam as a combined preparation for simultaneous, separate or sequential use for treatment of patients suffering from medical conditions mediated by tumor necrosis factor.
U.S. Pat. No. 5,603,921 discloses a medicated dental floss for controlling the bacterial activity associated with gingivitis. The floss incorporates an antimicrobial agent which, as a result of the flossing action, is deposited to the interdental area of the teeth. The slow dissolution of the antimicrobial agent ensures that effective levels of medication are attained for sustained periods, thereby reducing bacterial activity.
U.S. Pat. No. 5,688,516 discloses compositions and methods of employing compositions in flushing and coating medical devices. The compositions include selected combinations of a chelating agent, anticoagulant, or antithrombotic agent, with a non-glycopeptide antimicrobial agent, such as the tetracycline antibiotics. Methods for using these compositions for coating a medical device and for inhibiting catheter infection are also disclosed. Particular combinations include minocycline or other non-glycopeptide antimicrobial agent together with EDTA, EGTA, DTPA, TTH, heparin and/or hirudin in a pharmaceutically acceptable diluent.
Myers et al., J. Appl. Bacteriol 48:89-96 (1980) reported that taurolin--bis(1,1-dioxo-perhydro-1,2,4 thiadiazinyl) methane--is an antimicrobial compound formed by the condensation of two molecules of taurine with three of formaldehyde. It had been previously suggested that taurolin releases formaldehyde in contact with bacteria. The authors presented evidence that indicated that taurolin is mostly hydrolyzed in aqueous solution to release one molecule of formaldehyde and two monomeric molecules, 1,1-dioxo-perhydro-1,2,4-thiadiazine and its carbinolamine derivative. According to the article, a stable equilibrium was established. The authors concluded that antibacterial activity was not entirely due to adsorption of free formaldehyde, but also to reaction with a masked (or latent) formaldehyde, as the activity of taurolin was found to be greater than formaldehyde. The monomer was found to be only slightly active by comparison.
Gorman et al., J. Clin. Pharm. Ther. 12:393-399 (1987) reported on the examination of three antimicrobial agents, taurolidine, chlorhexidine, and povidone-iodine for microbial anti-adherence activity. Two adherence systems were investigated: an oral isolate of Candida albicans to human buccal epithelial cells and a urine isolate of E. coli to human uroepithelial cells. Each of the three agents exhibited significant anti-adherence activity, which was concentration dependent.
Root et al., Antimicrobial Agents and Chemotherapy 32(11):1627-1631(1988) reported that granulocytopenic patients with an intravascular catheter are at increased risk for infection with S. epidermis. During the intervals when the catheters are not being used for infusions, it is customary to maintain patency of the catheter lumen with a solution containing heparin. The authors showed that heparin does not inhibit the growth of S. epidermis isolated from the catheter of an infected patient. A 20-mg/mL solution of disodium EDTA, a chelating agent that effectively anticoagulates blood at this concentration, was shown to be bactericidal for an initial inoculum of 10.sup.3 CFU of staphylococci per mL in 24 hours. Vancomycin, an antibiotic that is often employed to treat Staphylococcus infections was also found to be bactericidal for initial inocula of 10.sup.3 CFU/mL at doses of 6.7 .mu.g/mL, a drug concentration in the therapeutic range. The authors recommended that EDTA be studied as a replacement for heparin solutions for the maintenance of intravenous catheters in granulocytopenic patients, in view of its low cost, effectiveness as an anticoagulant, and bactericidal activity.
Jones et al., J. Appl. Bacteriol. 71:218-227 (1991) examined the effects of three non-antibiotic, antimicrobial agents--taurolidine, chlorhexidine acetate, and povidone-iodine--on the surface hydrophobicity of the clinical strains E. coli, S. saprophyticus, S. epidermidis, and C. albicans. At concentrations reported to interfere with microbial-epithelial cell adherence, all three agents were found to alter the cell surface hydrophobicity. However, these effects failed to exhibit a uniform relationship. Generally, taurolidine and povidone-iodine treatments decreased the hydrophobicity of the strains examined, whereas chlorhexidine acetate effects depended upon the micro-organism treated.
Traub et al, Chemotherapy 39:322-330 (1993) examined taurolidine for bactericidal activity against a representative number of multiple-antibiotic-resistant bacterial isolates in broth as well as in the presence of bovine and human serum and fresh defibrinated human blood. The authors suggested that this antimicrobial substance might be employed for topical treatment of patients colonized or superficially infected by glycopeptide-resistant strains of E. faecium, S. aureus (GRMRSA), or by Enterobacteriaceae producing wide-spectrum .beta.-lactamases.
Willatts et al., Crit. Care Med. 23(6):1033-1039 (1995) reported that taurolidine had no beneficial therapeutic effect on the outcome of patients admitted to the intensive therapy unit of a university teaching hospital with sepsis syndrome, using clinical, bacteriologic outcomes, progression of endotoxemia, resolution of organ failure, and 28-day mortality rate as end points.
Darouiche et al., Nutrition 13(4)(suppl):26S-29S (1997) reported that the prevention of vascular catheter-related infection mostly centers around inhibiting the adherence to the catheter of microorganisms originating from either the skin or the catheter hub. They described two general approaches that can be used non-exclusively for the successful prevention of vascular catheter-related infection. The first approach does not use antimicrobial agents and includes measures such as placement and maintenance of vascular catheters by a skilled infusion therapy team and use of maximal sterile barriers. The second approach uses antimicrobial agents and involves the application of topical disinfectants such as chlorhexidine, use of silver-impregnated subcutaneous cuffs (for short-term central venous catheters), flushing catheters with a combination of antimicrobial and antithrombic agents, and coating of catheters with either antiseptic (chlorhexidine and silver sulfadiazine) or antimicrobial agents (minocycline and rifampin).
In a talk presented at the 30.sup.th annual meeting of the American Society of Nephrology, held Nov. 2-5, 1997 in San Antonio, Tex., Sodemann et al. reported on a four year trial of a gentamicin/sodium citrate mixture as an antibiotic-lock technique for salvage and prevention of catheter-related infections. They concluded that the replacement of catheters due to infection can be avoided by routine application of the concentrated gentamicin/citrate mixture and that even the salvage of intraluminally contaminated catheters is possible.
Notwithstanding the above-described contributions to the art, a need continues to exist for a safe and effective method for the prevention of infection and blood coagulation in patients whose illness requires the implantation of atrial catheters.